Obesity has become one of the most significant public health problems faced by the world today. Obesity is a serious health problem involving multiple factors. Evidence suggests obesity also involves appetite regulation and energy metabolism for control. In the United States, the prevalence of obesity has risen by 32% in adults and 40% in children over last two decades. Obesity is not just being overweight. It is a metabolic disorder due to the accumulation of excess dietary calories into visceral fat and the release of high concentrations of free fatty acids into various organs. As defined by the World Health Organization (WHO), a body mass index (BMI) greater than 25 is classified as overweight and a BMI greater than 30 as obesity. According to the global statistics, the population of overweight and obese individuals is approximately over 4.5 billion, of which approximately 27% is obese.
The increasing prevalence of obesity is a worldwide threat because it enhances the risk of various metabolic disorders and diseases such as insulin resistance, type 2 diabetes, hyperlipaemia, coronary heart disease, steatosis cardiovascular diseases, diabetes, chronic lower respiratory diseases, chronic hepatic disease and liver cirrhosis, hypertensive diseases, renal disease and NASH, NAFLD, and some type of cancers. Obesity not only increases mortality and causes huge medical complications, but also affects the life style.
The prevalence of NAFLD has increased in parallel with incidence of central obesity and is now the most common fatty liver disease in developed countries. NAFLD is defined as the presence of hepatic steatosis, with or without inflammation and fibrosis, in the absence of alcohol history. NAFLD is subdivided into NAFL and NASH. In NAFL, hepatic steatosis is present without evidence of significant inflammation, whereas in NASH, hepatic steatosis is associated with hepatic inflammation that may be histologically indistinguishable from alcoholic steatohepatitis.
The histological spectrum of NAFLD includes the presence of steatosis alone, fatty liver and inflammation. NASH is a more serious chronic liver disease characterized by excessive fat accumulation in the liver that induces chronic inflammation which leads to progressive fibrosis (scarring) that can lead to cirrhosis, hepatocellular carcinoma (HCC), eventual liver failure and death (Brunt et al., Am. J. Gastroenterol. 94:2467-2474, 1999; Brunt, Semin. Liver Dis. 21:3-16, 2001; Takahashi Y et al., World J Gastroenterol, 18:2300-2308, 2012).
NAFLD is generally recognized to be associated with metabolic syndrome such as insulin resistance, diabetes mellitus type 2, hyperlipidemia, hypertension and obesity. It is usually seen in people who are overweight or obese. NAFLD affects 30% of the world population and about 80% of obese people. NASH is more common in women and the most common cause is obesity. Recent studies also indicate that Overweight and obesity were strongly and progressively associated with an increased incidence of NAFLD.
NASH is a progressive, severe form of NAFLD. Over last 10-year period, up to 20% of patients with NASH will develop cirrhosis of the liver, and around 10% will suffer death related to liver disease. NASH progresses to cirrhosis in around 15-20% of affected individuals and is now one of the leading indications for liver transplantation in the United States. At present there are no approved therapies for NASH.
Despite the continuous increase in obesity incidences attributed to chronic liver diseases like NAFLD and NASH in all developed countries, limited pharmacological therapies are currently available to treat obesity or its related disorders in an efficacious and safe manner for the public.
Decreasing nutrient absorption, inhibition of appetite, and increasing thermogenesis are considered possible pharmacological methods for treating obesity. All of them have their substantial drawbacks. Decreasing nutrient absorption (e.g., inducing fat malabsorption) may cause gastrointestinal discomfort. Inhibition of appetite is usually expected to involve actions on brain structures, thus leading to problems of brain targeting and contamination of other tissues. Increasing thermogenesis may also have serious side effects.
Obesity Treatment
For effective treatment of obesity, current treatment modalities typically include diet and exercise programs, lifestyle management, pharmacotherapy and surgery. Treatment decisions are usually made based on severity of obesity, seriousness of associated medical conditions, subject risk status and subject expectations. Notable improvements in cardiovascular risk and the incidence of diabetes have been observed with weight loss of 5-10% of body weight, supporting clinical guidelines for the treatment of obesity that recommend a target threshold of 10% reduction in body weight from baseline values. Unfortunately, the available pharmacological therapies to facilitate weight loss fail to provide adequate benefit to many obese subjects because of side effects, contraindications or lack of positive response (National Heart, Lung and Blood Institute, Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report, NIH Publication No. 98-4083, September 1998).
Obesity Treatment by Medicines (Drugs)
Current treatment options for type IIb hyperlipidemia mostly seen in obese persons are limited. While statins are very effective at lowering LDL-C, they are generally not very effective at lowering triglyceride levels. Some statins at high dose levels, for example atorvastatin at 80 mg, significantly lower triglyceride levels. However, high dose statin therapy can cause muscle pain (myalgia) and is often not well tolerated by patients. In addition, high dose statin therapy carries with it an increased risk for serious muscle toxicity such as rhabdomyolysis. Another treatment which typically includes administering a combination of a cholesterol lowering agent, such as a statin, and a triglyceride lowering agent, such as a fibrate, niacin or fish oil. However, the commonly used triglyceride lowering agents may not be convenient or may not be well tolerated, for example, fibrates are associated with myalgia and an increased risk of muscle toxicity, fish oil needs to be taken multiple times daily, and niacin causes flushing particularly when administered in combination with statins.
The most popular over-the counter drugs for the treatment of obesity are phenylpropanolamine and ephedrine, and the most popular prescription drug, is fenfluramine. These drugs were withdrawn from the marketplace as a result of safety concerns. Drugs currently approved for the long-term treatment of obesity fall into two categories:
1. Amphetamines and sibutramine that act on the hypothalamus to control appetite stimulation in the CNS. (CNS appetite suppressants).
2. Orlistat that is a lipase inhibitor that blocks gastrointestinal absorption of fat and decreases energy uptake (Gut Lipase Inhibitors [Cooke et al 2006 Nat Rev Drug Discov 5:919-31].).
Common side effects associated with these drugs include tachycardia, hypertension, fecal incontinence and/or cardiac valvopathy, making anti-obesity drug development of paramount importance.
Although appetite suppressants and gut lipase inhibitors work through very different mechanisms, they share the same overall goal of reducing body weight secondary to reducing the amount of calories that reach the systemic circulation. Unfortunately, these indirect therapies produce only a modest initial weight loss (approximately 5% compared to placebo) that is usually not maintained. After one or two years of treatment, most patients return to or exceed their starting weight. In addition, most approved anti-obesity therapeutics produce undesirable and often dangerous side effects that can complicate treatment and interfere with a patient's quality of life.
For example, orlistat, sibutramine, and liraglutide, i.e., compounds used so far for treating metabolic syndrome or obesity, cause a series of severe side effects. In particular, the European Medicines Agency (EMA) has reviewed the safety and effectiveness of sibutramine and came to the conclusion that the benefits of sibutramine do not outweigh its risks, and that all marketing authorizations for medicines containing sibutramine should be suspended throughout Europe (cf. “Questions and answers on the suspension of medicines containing sibutramine—Outcome of a procedure under Article 107 of Directive 2001/83/EC”, EMA/808179/2009). Furthermore, the primary side effects of orlistat comprise steatorrhea, fecal incontinence and the inhibition of absorption of fat-soluble vitamins thereby forcing the patient who takes orlistat to:
(i) avoid foods with high fat content and
(ii) separately take dietary supplements containing fat-soluble vitamins and other fat-soluble nutrients.
Obesity Treatment by Surgery
Bariatric surgery may be considered as a weight loss intervention for subjects at or exceeding a BMI of 40 kg/m2. Subjects with a BMI of 35 kg/m2 and with an associated serious medical condition are also candidates for this treatment option. Unfortunately, postoperative complications commonly result from bariatric surgical procedures, including bleeding, embolism or thrombosis, wound complications, deep infections, pulmonary complications, and gastrointestinal obstruction; reoperation during the postoperative period is sometimes necessary to address these complications. Major and serious adverse outcomes associated with bariatric surgery are common, observed in approximately 4 percent of procedures performed (including death in 0.3 to 2 percent of all subjects receiving laparoscopic banding or bypass surgeries, respectively).
Lifestyle
The most important recommendations given to persons with this disease are aerobic exercise, manipulations of diet and eating behavior, and reducing their weight (if obese or overweight). Since lifestyle modification has not been proven effective, therapeutic strategies are required. However, potent and safe therapeutic strategies to combat these diseases are inadequate. Currently there are no effective pharmaceutical treatments for this pandemic problem. Although surgical procedures can reduce weight by 50-90%, it is restricted due to the risk of surgery and associated side effects. Therefore, there is still a need for the development of alternative and/or improved therapeutic strategies for the treatment obesity and its related disorders.
NAFLD Treatment by Medicines
Treatment of the symptoms of NAFLD/NASH include lipid lowering medications, insulin sensitizing (medications), and the reduction of inflammation via anti-oxidant medications (such as vitamin E, selenium, and betaine), anti-apoptotic medications, and anti-cytokine medications, it may also include reduction of total cholesterol level, weight loss, control of any underlying diabetes, reduction or elimination of alcohol consumption, treatment of high blood pressure, and regular exercise. (American College of Gastroenterology; WebMD).
The most important recommendations given to persons with this disease are to reduce their weight (if obese or overweight), follow a balanced and healthy diet, increase physical activity, avoid alcohol, and avoid unnecessary medications. Another experimental approach to treat NAFLD/NASH is the use of newer antidiabetic medications—even in persons without diabetes. The primary goal for the clinical management of NAFLD/NASH is to reduce the risk of cardiovascular disease and type II diabetes. The risks of these diseases are highly diminished by reducing triglyceride levels in the blood including LDL cholesterol, reducing blood pressure, and reducing blood glucose levels.
Current treatments target either insulin resistance (e.g., metformin, thiazolidinediones) or insulin release from the beta cell (e.g., sulfonylureas, exenatide). However, these treatments suffer from various deficiencies, including side effects, limited efficacy, and undesirable long-term effects. However, there are currently no approved treatments for NASH/NAFLD itself.
NAFLD may go on to cause cirrhosis or liver cancer and as such early and effective treatment is essential. Otherwise, Liver transplantation is the only curative option for patients with advanced liver cirrhosis. However, this procedure can only be applied to a minority of patients due to the presence of surgical contraindications and organ scarcity.
While there are been continued advancements, there remains a pressing need for more safe, effective and improved therapies for treatment of obesity and its related diseases like NASH/NAFLD. Thus, a naturally occurring, orally active compound(s) that will reduce obesity and its related disorders is desired.
Requirement of Natural Active Ingredients
OEA is an endogenous peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, and is the result of a combination of oleic acid and ethanolamine. OEA is a naturally occurring lipid mediator that inhibits food intake and body weight gain and therefore has been a molecule of recent intense scientific interest in the search for therapeutic strategies for the treatment of human obesity. OEA is a fatty acid metabolite that is produced by the gut to signal to the brain the sensation of being full, thus to regulate appetite and healthy body fat. OEA helps regulate lipid metabolism, helps control hunger by sending appetite suppressant messages to the brain and has been shown to help lower both triglyceride and blood cholesterol levels.
β-aminoisobutyric acid (BAIBA) is a non-protein β-amino acid, a catabolite of thymine, which is further degraded into propionyl-CoA, methylmalonyl-CoA and succinyl-CoA within mitochondria, especially in liver. BAIBA can also be generated by catabolism of the branched-chain amino acid valine. BAIBA reduces body fat percentage through increased fatty acid oxidation (FAO) and decreased de novo lipogenesis in liver in mice. BAIBA enhances the browning of white adipose tissue and FAO in the liver via peroxisome proliferator-activated receptor α (PPARα), and may contribute to exercise-induced protection from metabolic diseases. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors. BAIBA may thus contribute to exercise-induced protection from metabolic diseases.
Anti-oxidants also play an important role in the treatment of obesity. An increase in leptin leads to an increase in adhesion molecules; adipocytes recruit monocytes which are then transformed into macrophages. Macrophages are capable of producing large amounts of oxidants such as peroxynitrite. An obesity-associated increase in oxidative stress has been examined by different methods-measurements of thiobarbituric reactive acid substances (TBARS), malondialdehyde formation (MDA), oxidized LDL, oxidized urinary albumin, peroxide estimated from reactive oxygen assays, and the formation of carbonyl proteins in erythrocytes. A review of the literature shows that in most studies, obesity and type 2 diabetes are associated with an increase in oxidative stress. Thus, the oxidative stress is also associated with weight loss rather than diet alone. Given that obesity and type 2 diabetes are associated with increased oxidative stress, there is a need of an anti-oxidant to manage the excessive generated free radicals or toxins.
α-Glucosidase inhibitors can be used as a new class of antidiabetic drug. By competitively inhibiting glycosidase activity, these inhibitors help to prevent the fast breakdown of sugars and thereby control the blood sugar level. In the 1980s, α-glucosidase inhibitors became a new class of antidiabetic drug. α-Glucosidase inhibitors slow down the process of digestion and absorption of carbohydrates by competitively blocking the activity of glucosidase. All of them contain sugar moieties and their synthesis involves tedious multistep procedures. Moreover, clinically chemically synthesized α-glucosidase inhibitors have been associated with serious gastrointestinal side effects. Therefore, it is necessary to search for alternatives that can display α-glucosidase inhibitory activity but without side reactions.
I-deoxynojirimycin (DNJ) is a glucose analogue with a secondary amine group instead of an oxygen atom in the pyranose ring of glucose. DNJ potently inhibits α-glucosidase in the small intestine by binding to the active center of α-glucosidase. DNJ has also been found in the leaves and fruits of M. alba, suggesting that the legendary antidiabetic effect of mulberry leaves may be attributed to DNJ, which inhibits postprandial hyperglycemia by inhibiting α-glucosidase in the small intestine. Use of DNJ-rich mulberry leaf extract modestly decreased Triglyceride level after intake of long duration (12 weeks), although the decrease was not statistically significant. Several studies have demonstrated that phytochemicals from natural resources provide new opportunities for treating diabetes. Mulberry leaf extracts have been used in China and other Asian countries to treat diabetes on the basis of reports of antidiabetic effects in experimental animals.
Cannabinoid-based medicines have therapeutic potential for the treatment of pain. Augmentation of levels of endocannabinoids with inhibitors of fatty acid amide hydrolase (FAAH) is analgesic. Fatty acid amide hydrolase (FAAH) is a membrane-bound serine hydrolase that belongs to the amidase signature family of hydrolases. FAAH enzyme breaks down fatty acid amides such as anandamide (N-arachidonoylethanolamine), N-oleoylethanolamide (N-OEA), N-palmitoylethanolamide (N-PEA) and oleamide. FAAH belongs to a large and diverse class of enzymes referred to as the amidase signature (AS) family. FAAH Inhibitors are a class of molecules that inactivate the Fatty Acid Amine Hydrolase Enzymes by preventing the hydrolysis of anandamide, oleoylethanolamide and palmitoylethanolamide and thereby increasing their endogenous levels. Known chemically synthesized FAAH inhibitors are BIA 10-2474, URB524, URB-597, URB694, URB937, etc. These inhibitors are disclosed in Colombano et al. in the published article titled “O-(Triazolyl) methyl carbamates as a novel and potent class of fatty acid amide hydrolase (FAAH) inhibitors” and in the published article by Otrubova et al. titled “The discovery and development of inhibitors of fatty acid amide hydrolase (FAAH).